HIV Associated Dementia (HAD) is a strikingly debilitating neurological consequence of HIV infection. Although its cause is still unclear, it is thought that HIV replication within immune cells of the Central Nervous System (CMS) results in their dysfunction, leading indirectly to neuronal death. While Interferon (IFN) (3, a cytokine mediator of the innate immune response in the brain, has been shown to be effective at preventing HIV replication, the effect is transient. HIV is eventually able to overcome its antiviral effects and resume replication, an event which heralds progression to HAD. Therefore, it is critical that the mechanism by which HIV evades this protective immune response be determined. Recently, numerous viral and bacterial pathogens, including HIV, have been shown to induce the expression of a family of negative regulators of cytokine function, the Suppressors Of Cytokine Signaling (SOCS). The goal of this proposal is to determine whether SOCS protein expression in the HIV-infected brain mediates the loss of IFN(3's ability to suppress HIV replication, and therefore promotes progression to HAD. First, it must be determined whether SOCS expression occurs in the HIV-infected brain. This will be examined in vivo by evaluation of SOCS protein expression in post-mortem HAD brain tissue. In addition, HIV Tat-treatment of CNS-relevant primary human and murine cells will be used in vitro to determine the mechanism of SOCS induction. Second, it must be determined whether SOCS protein expression functions to inhibit IFN(3 signaling, and thereby promote HIV replication in the brain. IFN0 signaling will be examined in vitro, in primary human and murine cells, at the level of STAT phosphorylation, target gene induction, and inhibition of HIV replication. The effect of both SOCS protein overexpression and deficiency will be evaluated to determine whether SOCS expression is sufficient to mediate inhibition of IFN(3's antiviral response. These studies will provide novel insight into the mechanism by which HIV is able to evade the innate immune system in the CNS. PUBLIC HEALTH RELEVANCE: This work seeks to determine whether HIV replication in the brain, and therefore progression to HIV Associated Dementia (HAD), is aided by Suppressor Of Cytokine Signaling (SOCS) proteins. Defining the potential mechanism by which these proteins allows HIV to evade the brain's protective immune response will allow for the development of therapies to strengthen this defense.